The gamma chain gene of the IL-2 receptor (IL2RG) is responsible for X-linked severe combined immunodeficiency (XSCID), the most common form of human SCID. The only available lifesaving treatment at present is bone marrow transplantation, but drawbacks of this include the lack of HLA matched related donors, poor post-transplant B cell function, graft vs. host disease, and late T cell loss. In vivo positive selection for cells with intact IL2RG makes XSCID a promising disease for retroviral gene therapy delivered to autologous bone marrow stem cells. This strategy was pursued by comparing different retrovirus constructs for titer, gamma chain expression in transduced cell lines, correcting the functional defect in cell lines from XSCID-affected patients with defined IL2RG defects, and monitoring the development of cord blood stem cells transduced with IL2RG retroviruses in SCID mice. These experiments have shown significant cell surface expression of the gamma chain protein in previously deficient cell lines from SCID patients. The availability of a large panel of patient cell lines will permit evaluation of potential dominant negative mutations. SCID patients prenatally diagnosed with defined IL2RG mutations have had their cord blood collected at birth for experimental transduction and evaluation of lymphocytogenesis. Canine expression of transduced human gamma chain resulting was studied in collaboration with researchers at the U. of PA School of Vet. Med. Normal dogs pretreated with cytokines and sublethal irradiation have achieved unprecidented levels of long-term expression of human gamma chain for over one year.